The protocols involved in this project are as follows: 02-M-0120, 03-M-0175, 88-M-0131, 92-M-0174. This report includes work arising from the following protocols: NCT00030147, NCT00060736, NCT00001231, and NCT00001322. A role of estradiol withdrawal in the onset of mood disorders in some perimenopausal women has been suggested indirectly by the clustering of depressive episodes during the late menopause transition (the stage of ovarian aging associated with maximal decline of ovarian estradiol secretion) and by estradiol's antidepressant efficacy in perimenopausal depression. Nonetheless, there is no direct evidence that estradiol withdrawal precipitates depressive episodes in those women who develop depression during the perimenopause. In these studies, first we examine the effects of estradiol withdrawal and the recent onset of hypogonadism on mood symptoms in asymptomatic premenopausal women. Second, we investigate what factors influence the development of depression during estradiol withdrawal. If the onset of ovarian failure and/or the development of vasomotor symptoms and disturbed sleep during the menopause are sufficient to trigger depression, then the induction of a hypogonadal state should be accompanied by depressive symptoms in a substantial number of women. We administered a GnRH agonist for two to three months to 72 regularly cycling, healthy premenopausal women (age: mean SD = 33.0 8.0 years) with no medical or gynecologic illness. The absence of current or past psychiatric illness was confirmed by SCID interview, and daily symptom ratings were completed prior to the study to confirm the absence of significant menstrual cycle-related mood or behavioral symptoms. Mood symptoms were measured by the BDI and a daily self-report symptom rating form. We observed only four women (5.6% of the sample) who reported BDI scores > 10 (suggestive of clinically significant symptoms of depression), and in only one of these women did the elevated BDI scores persist beyond two weeks duration (Ben Dor et al, in press). In contrast to the relative absence of depressive symptoms in these women, we did observe the significant appearance of several symptoms including nocturnal hot flushes, disturbed sleep, and diminished libido (this latter finding is consistent with a subsample of these women in whom significant reductions in libido were observed in approximately 30% of the sample). Neither plasma estradiol levels nor the severity of hot flushes correlated with mood rating scores. Thus, in otherwise healthy women the induction of neither hypogonadism nor hot flushes (with an accompanying sleep disturbance) uniformly precipitates depressive symptoms. Finally, the fact that our results stand in marked contrast to multiple case reports describing the onset of clinically significant depression during GnRH agonist treatment of several gynecologic disorders (e.g., endometriosis, uterine fibroids) suggests several biological factors (e.g., estrogen receptor signaling) that need to be studied as potential risks for the onset of depression in the context of estradiol withdrawal and hypogonadism. In a second study, we evaluate the effects of the acute withdrawal of estradiol therapy in older postmenopausal women with and those without a past perimenopausal depression. Estradiol withdrawal induces depressive symptoms in women with a past perimenopausal depression, but not in those without such a history. In women with a past depression during the perimenopause, estradiol withdrawal is associated with a significant increase in depressive symptoms compared with those who were maintained on estradiol therapy. Additionally, no significant depressive symptoms emerged in the women lacking a history of depression. These data are consistent with those from epidemiologic studies showing that, for a subgroup of women, the endocrine events of the late menopause transition represent an important trigger for mood destabilization and the onset of depression. Both the markers of this risk and the mechanisms underlying estradiol withdrawal-induced depressive symptoms remain to be identified. The results of the Womens Health Initiative (WHI) have deterred many women from using estrogen therapy, and many women and their physicians are concerned about the long-term risks of estrogen therapy. In a previous study, we demonstrated the antidepressant effects of the short-term administration of estradiol in women with perimenopausal depression. We now examine the effects on mood and behavior of two compounds that for many women represent alternatives to traditional estrogen therapy. Specifically, selective estrogen receptor modulators (SERMs) and phytoestrogens (plant-derived estrogen-like compounds) have become available and are reported to display both tissue-specific profiles of estrogen agonist and antagonist actions and differential affinities from estradiol for the two forms of estrogen receptor. Preliminary results of this trial, demonstrate that after eight weeks of either estradiol or raloxifene (but not a plant-based phytoestrogen compound), mood rating scores were significantly decreased compared with baseline scores and significantly lower than scores in women receiving placebo. Thus, we not only have replicated our previous demonstration of the therapeutic efficacy of estradiol in perimenopausal depression, but in addition, we have identified a potential new therapeutic agent (raloxifene) in this condition. Comparable efficacy of raloxifene to that of estradiol would provide an alternative therapeutic option with a more acceptable profile of long-term side effects. As phytoestrogens are already commonly recommended, and widely used for the treatment of mood symptoms, further clarification of their mood effects has significant public health implications. In future studies, we will examine the antidepressant/anxiolytic efficacy of selective estrogen receptor beta agonists (when available for human use) in women with perimenopausal depression. In a separate set of studies in collaboration with Dr. Laurence Nelson within NICHHD, we investigate the relationship between ovarian failure, deficiencies in testosterone production, and depression in younger women with karyotypically, normal, 46XX spontaneous (i.e., idiopathic) primary ovarian insufficiency (POI). In a prior study, we identified a significantly greater lifetime prevalence of depression in adult women with POI than that reported in both the general population, and in gynecologic or general medical outpatient settings. It has been suggested that the accompanying loss of ovarian testosterone production increases the risk for depression in POI (and in perimenopausal depression). Thus we performed a randomized, placebo-controlled, trial of physiologic testosterone replacement in128 women with POI. Results of this trial clearly show the lack of efficacy of testosterone on mood symptoms, quality of life, and self-esteem in POI. A better understanding of the nature of the association between POI and depression could identify candidate genes and physiological processes that may inform both our understanding of the relationship between depression and POI, as well as the association between depression and the normally-timed menopause transition.